Prognosis after Local Recurrence in Patients with Early-Stage Breast Cancer Treated without Chemotherapy.

BACKGROUND: Many women with early-stage breast cancer are predicted to be at sufficiently low risk for recurrence that they may forego chemotherapy. Nevertheless, some low-risk women will experience a local recurrence, and for them the risk of death increases significantly thereafter. The utility of initiating chemotherapy at the time of local recurrence has not been adequately addressed. The purpose of this study is to identify, in a hospital-based series of patients with early-stage breast cancer who were not treated with chemotherapy, those factors which predict death post local recurrence. METHODS: We identified 135 women who were diagnosed with early-stage breast cancer (node-negative, <5 cm) and who did not receive chemotherapy at diagnosis and who developed a local recurrence. They were diagnosed between 1987 and 2000 and treated at Women's College Hospital. For each patient, we abstracted information on the initial cancer (age at diagnosis, tumour size, tumour grade, ER status, PR status, HER2 status, lympho-vascular invasion, type of surgery, use of radiotherapy, tamoxifen and chemotherapy), the time from initial diagnosis to local recurrence and treatment at recurrence. The Kaplan-Meier method was used to estimate the ten-year actuarial risk of breast cancer death post recurrence. A Cox proportional hazards model was used to estimate multivariate hazard ratios for the various factors. RESULTS: Among the 135 women in the cohort, the mean time from initial diagnosis to local recurrence was 7.8 years (range: 0.3 to 22.6 years). A total of 38 of the 135 women (28.1%) died of breast cancer a mean of 5.3 years after experiencing the local recurrence (range: 0.3 to 17 years). The ten-year breast cancer survival post local recurrence was 71% and the 15-year survival was 65%. In a multivariate analysis, it was found that factors that were significantly associated with death after local recurrence were (1) PR-negative status, (2) young age at diagnosis (<40 years) and (3) time to local recurrence less than 2 years. Nine percent of women received chemotherapy at the time of local recurrence. CONCLUSIONS: For breast cancer patients with a low baseline risk of mortality, the risk of death after an isolated local recurrence is substantial. Systemic treatment at the time of local recurrence needs further study.

Countercurrents: DCIS or Cancer? Why All the Confusion?

At present, women with ductal carcinoma in situ are counseled that they have a pre-malignant condition which carries the possibility of progression to a fully malignant breast cancer. However, in most cases, the treatment of DCIS resembles that of a small invasive breast cancer and this is a source of confusion to many. In order to properly evaluate the benefit of radiotherapy, mastectomy and contralateral mastectomy, it is necessary to consider the risks of ipsilateral invasive cancer and of contralateral breast cancer in women with DCIS and with small invasive breast cancer. Several registry-based studies indicate that the risks of ipsilateral and contralateral cancer are similar in the two conditions and therefore a similar approach to treatment is rational.

International variation in breast cancer incidence and mortality in young women.

PURPOSE: Breast cancer in young women (< 40 years) is rare and carries a poor prognosis relative to breast cancer in older women. Most studies examining global breast cancer patterns do not describe the trends in young women specifically. METHODS: Data from GLOBOCAN 2018 were used to compare breast cancer incidence and mortality rates among younger (ages 0-39) vs. older (ages 40+) women across 185 countries. The coefficient of variation (the ratio of the standard deviation to the mean) was used to quantify relative variability. RESULTS: The risk of developing breast cancer to age 39 ranged from 0.13% in Guinea to 0.95% in South Korea (coefficient of variation: 46%), and the risk of death from breast cancer to age 39 ranged from 0.02% in China to 0.72% in Cameroon (coefficient of variation: 81%). In contrast, the risk of developing breast cancer to age 74 ranged from 1.5% in Mozambique to 12.2% in Belgium (coefficient of variation: 50%), and the risk of death from breast cancer to age 74 ranged from 0.65% in South Korea to 3.0% in Somalia (coefficient of variation: 36%). CONCLUSIONS: Among young women, breast cancer mortality rates varied more worldwide than breast cancer incidence. In contrast, among older women/women of all ages, breast cancer incidence varied more than breast cancer mortality. Further research is required to examine the impact of stage at diagnosis, clinicopathologic features, and treatments received, on variations in the survival and mortality of breast cancer in young women around the world.

A Validation of Methods for the Evaluation of Observational Studies of Screening Mammography: An Exploratory Analysis Based on Simulating Screening Cohorts.

BACKGROUND: The degree of confidence one should place on non-randomised observational trials studies which estimate the benefit of screening depends on the validity of the analytic method employed. As is the case for all observational trials, screening evaluation studies are subject to bias. The objective of this study was to create a simulated data set and to compare four analytic methods in order to identify the method which was the least biased in terms of estimating the underlying hazard ratio. METHODS: We simulated a cohort of 100,000 women who were accorded US national rates of breast cancer incidence and breast cancer mortality over their lifetime. We assigned at random one-half of them to initiate mammography screening between ages 50 and 60. We used four different analytic approaches to estimate the hazard ratio under a null model (true HR = 1.0) and under a protective model (true HR = 0.80). Two models used the entire data set (with and without including mammography as a time-dependent covariate) and two models invoked matching of screened women with unscreened women (with and without excluding of women who had a mammogram after study initiation). For each of the four analytic methods, we compared the observed hazard ratio with the true hazard ratio. We considered an analytic method to be valid if the observed hazard ratio was close to the true hazard ratio. RESULTS: Two simple analytic methods generated biased results that led to spurious protective effects observed when none was there. The least biased method was based on matching screened and unscreened women and which emulated a randomized trial design, wherein the unexposed control had no mammogram prior to study entry, but she was not excluded or censored if she had a mammogram after the index date. CONCLUSION: There is no single ideal method to analyze observational data to evaluate the effectiveness of screening mammography (ie, which generates an unbiased estimates of the underlying hazard ratio) but designs which emulate randomised trials should be promoted.

Association of a Diagnosis of Ductal Carcinoma In Situ With Death From Breast Cancer.

Importance: It is not clear to what extent a diagnosis of ductal carcinoma in situ (DCIS) impacts a woman's lifetime risk of dying of breast cancer. Under ideal circumstances, treatment will eliminate the risk of invasive ipsilateral recurrence and prevent subsequent mortality from breast cancer. The risk of dying of breast cancer after a diagnosis of DCIS had not been compared with that of women without cancer in the general population. Objective: To determine the risk of death from breast cancer in a large cohort of patients treated for DCIS and to compare the risk with that of women in the general population. Design, Setting, and Participants: This cohort study included data for women who had first primary DCIS diagnosed between 1995 and 2014 from the Surveillance, Epidemiology and End Results (SEER) registries database. Women with DCIS underwent surgical treatment, and approximately half also received radiotherapy. These women were followed from the date of DCIS diagnosis until death from breast cancer or date of last follow-up. Women in the general population without breast cancer were analyzed as controls. Follow-up information was available up to December 2016. The data were analyzed in March 2020. Exposures: Patients with DCIS who underwent surgical treatment. Main Outcomes and Measures: Breast cancer death was the main outcome. Standardized mortality ratios were estimated by comparing deaths from breast cancer among women diagnosed with DCIS with expected deaths from breast cancer among women in the general population who did not have cancer. Expected probability of death from breast cancer in the general population was calculated by an incidence-based mortality approach using standardized SEER-based incidence and case-fatality rates. Probability of breast cancer death was estimated based on the assumption that a cancer-free control was cancer free on the date the woman with DCIS was diagnosed and was studied until the end of follow-up. Results: A total of 144 524 women diagnosed with first primary DCIS were included (mean [SD] age at diagnosis, 57.4 [11.0] years). There were 1540 deaths from breast cancer in the cohort. Based on SEER-based incidence and case-fatality rates, 458 breast cancer deaths were expected in an equivalent number of cancer-free women from the general population with equal follow-up. The standardized mortality ratio for death from breast cancer among women with DCIS was 3.36 (95% CI, 3.20-3.53). The elevated risk of death persisted more than 15 years after diagnosis. Conclusions and Relevance: In the population studied, the risk of dying of breast cancer was increased 3-fold after a diagnosis of DCIS. This suggests that our current treatment focus on preventing invasive recurrence is insufficient to eliminate all deaths from breast cancer after DCIS.

Retesting of women who are negative for a BRCA1 and BRCA2 mutation using a 20-gene panel.

BACKGROUND: The value of retesting women who previously tested negative for a pathogenic variant (mutation) in BRCA1 and BRCA2 using an expanded panel of breast and ovarian cancer genes is unclear. METHODS: We studied 110 BRCA1/2-negative women who were retested using a panel of 20 breast and/or ovarian cancer susceptibility genes at the Advanced Molecular Diagnostics Laboratory (AMDL) at Mount Sinai Hospital in Toronto between March 2017 and March 2019. All patients had previously tested negative for BRCA pathogenic variants at the AMDL between January 2012 and March 2018 and were subsequently referred for retesting by their physician. RESULTS: Overall, six pathogenic variants in genes other than BRCA1 and BRCA2 were found (prevalence 5.5%). There were two pathogenic variants found in RAD51C, and one found in each of BRIP1, PALB2, PMS2 and PTEN. The prevalence of pathogenic variants was 6.5% for women affected with cancer (6 of 93), including 4.9% for women with breast cancer (4 of 82) and 22.2% for women with ovarian cancer (2 of 9). None of the 17 unaffected women had a clinically significant or pathogenic variant. There were 44 women (40%) for whom the result of the panel test was inconclusive due to the detection of a variant of uncertain significance. CONCLUSIONS: Our findings indicate that the retesting of BRCA1/2-negative individuals with an expanded panel of 20 breast and ovarian cancer genes can produce clinically relevant results, with a yield of 5.5% for pathogenic variants in genes other than BRCA1 and BRCA2.

Predictors of time to death after distant recurrence in breast cancer patients.

BACKGROUND: After experiencing a distant recurrence, breast cancer patients have a poor prognosis; fewer than 5% survive for ten or more years. However, the time to death is highly variable, ranging from a few months to many years. The purpose of this study is to identify, in a large hospital-based series of patients with early-stage breast cancer, factors which predict survival after distant recurrence. METHODS: We studied a cohort of 2312 women diagnosed with invasive breast cancer at Women's College Hospital between 1987 and 2000 (stages I-III). For each patient, we abstracted information on age at diagnosis, the initial presentation of the cancer (tumour size, lymph node status, tumour grade, ER status, PR status, HER2 status), treatment (surgery, radiotherapy, chemotherapy, hormone therapy), the dates of all tumour recurrences (local, regional, distant) and the dates and causes of death. The Cox proportional hazards model was used to estimate the univariate and multivariate hazard ratios for death from breast cancer following distant recurrence associated with the various tumour features. RESULTS: After a mean follow-up of 12.8 years from diagnosis, 523 distant recurrences were recorded among women in the cohort (23% of 2312) and 604 women (26%) died of breast cancer. For the 484 women who had a distant recurrence on record and died of breast cancer, the mean time from distant recurrence to death was 2.0 years (range 0-11.9 years). In a multivariate analysis, only two factors were significantly associated with time to death after distant recurrence: ER status (positive vs. negative, HR 0.56; 95% CI 0.43-0.71; p < 0.0001) and tumour grade (high vs. low, HR 1.87; 95% CI 1.16-3.01; p = 0.01). Among ER-negative patients (N = 175), high tumour grade and a short time from diagnosis to distant recurrence were associated with a rapid time to death. Among ER-positive patients (N = 336), there was no significant independent predictor of time from recurrence to death. CONCLUSIONS: Among ER-negative breast cancer patients, the time to death after distant recurrence was predictable to some extent; women with a short time from diagnosis to recurrence and/or with high-grade tumours were more likely to succumb to breast cancer within 3 years. Among ER-positive breast cancer patients who experience a distant recurrence, the time to death varies substantially and between patients could not be predicted by tumour factors or treatment. This suggests that for ER-positive patients, the factors that determine the time from diagnosis to distant recurrence do not predict the course of the cancer post-recurrence.

Time to death in breast cancer patients as an indicator of treatment response.

PURPOSE: To describe the mortality experience of women who die of breast cancer in the 20-year period post-diagnosis using various metrics, including annual mortality rates, Kaplan-Meier survival curves and time-to-death histograms. METHODS: We generated three visual representations of SEER-based and hospital-based breast cancer patient cohorts using three different metrics of mortality. RESULTS: The greatest impact of most prognostic factors was on the probability of latent metastases present after treatment, but for some factors the primary impact was on the time to death for those women with metastases. CONCLUSIONS: The use of time-to-death statistics to display mortality benefits for treated versus untreated women helps facilitate the distinction between treatments which increase the likelihood of cure and treatments that delay cancer growth.

The relationship between tumour size, nodal status and distant metastases: on the origins of breast cancer.

BACKGROUND: In patients with breast cancer, increasing tumour size at diagnosis is associated with an increased likelihood of axillary lymph node involvement and increased breast cancer-specific mortality. However, this relation is based on studies which combine all tumours smaller than 1.0 cm in a single category and all tumours larger than 5.0 cm in another category. This coarse classification may obscure a nuanced description of the effects of tumour size across the full range of possible sizes. METHODS: We examined the relationship between primary tumour size, lymph node status and distant metastases in a cohort of 819,647 women diagnosed with first primary invasive breast cancer from 1990 to 2014 in the Surveillance, Epidemiology and End Results (SEER) registries database. All patients in the cohort had a known primary tumour size between 1 and 150 mm in greatest dimension. Primary tumour size was examined as a continuous (1-150 mm) and categorical variable (15 size groups; 10-mm intervals). For each 1- or 10-mm size group, we determined the proportion of patients with positive lymph nodes at diagnosis, the proportion of patients with distant metastases at diagnosis and the actuarial cumulative risk of breast cancer-specific mortality at 15 years from diagnosis. RESULTS: Among 819,647 patients with invasive breast tumours between 1 and 150 mm in size, there was a non-linear correlation between increasing tumour size and the prevalence of lymph node metastases at diagnosis (% node-positive), the prevalence of distant metastases at diagnosis (% stage IV) and the 15-year rate of breast cancer-specific mortality across the entire size spectrum. For very small tumours (under 10 mm) and for very large tumours (larger than 60-90 mm) there was little correlation between tumour size and metastasis risk. CONCLUSIONS: The relationship between tumour size, lymph node status and distant metastases in patients with invasive breast cancer is not linear. This calls into question the conventional model that the capacity for a primary breast tumour to metastasize increases as the tumour enlarges.

A comparison of two models for breast cancer mortality for women with ductal carcinoma in situ: an SEER-based analysis.

BACKGROUND: Approximately 1% of patients with ductal carcinoma in situ (DCIS) will die of breast cancer within 10 years. Women who develop an invasive breast cancer after DCIS have a much greater risk of dying than those who do not and it is often stated that these deaths are a consequence of metastases from the invasive in-breast recurrence. This progression is the result of a two-step process: first local invasive recurrence and then spread beyond the breast. A large proportion of women who die of DCIS have no record of invasive recurrence. We used SEER data and a simulation approach to test whether the actual mortality data are consistent with the two-step model. METHODS: First, we constructed Kaplan-Meier mortality curves for all patients with pure DCIS and with small node-negative invasive breast cancers in the Surveillance, Epidemiology and End Results (SEER) registries database (1998-2014). We then constructed, through simulation, theoretical breast cancer mortality curves. To model the two-step scenario, we applied the annual incidence rates of incident invasive cancer following DCIS and of death from invasive cancer after DCIS to a theoretical cohort of 100,000 women. RESULTS: The observed 15-year breast cancer-specific mortality rate for patients with pure DCIS in the SEER database was 2.0%. The expected mortality for DCIS patients (assuming a two-step process) was only 1.1% at 15 years. Assuming the mortality rates following DCIS were one-half of those observed for patients with small invasive breast cancers, the expected mortality at 15 years post-DCIS was 2.1%. CONCLUSIONS: In the SEER database, we observed far more deaths from DCIS than would be expected under a model where all deaths from breast cancer occur amongst women who experience an invasive local recurrence. This lends support to the hypothesis that DCIS mortality is not restricted to those women who experience an in-breast invasive cancer and that DCIS has properties similar to small invasive breast cancers.

Is invasion a necessary step for metastases in breast cancer?

PURPOSE: To review the empirical evidence to support the conventional (sequential) model of breast cancer progression, which is based on the paradigm that cancer passes through several stages, including an in situ stage prior to an invasive stage, and thereafter (in some cases) disseminates to the lymph nodes and distant organs. METHODS: We review the cancer literature of the last 50 years which relates to the prevention of invasive breast cancer (through radiotherapy or surgery) and reductions in the mortality for breast cancer. RESULTS: For both invasive cancers and DCIS, the literature indicates that prevention of in-breast invasive recurrences does not prevent death from breast cancer. Moreover, the presence of residual cancer cells in the breast after breast-conserving surgery does not compromise the cure rate. CONCLUSION: We propose an alternate (parallel) model of breast cancer wherein there is a small pool of cancer stem cells which have metastatic potential from their inception and which disseminate synchronously through several routes-to the breast stroma, to the lymph nodes and to distant organs. Cancer cells which disseminate to the breast give rise to cells which make up the bulk of the tumour mass but these are not the source of the distant metastases.

Association of Radiotherapy With Survival in Women Treated for Ductal Carcinoma In Situ With Lumpectomy or Mastectomy.

Importance: Patients with ductal carcinoma in situ (DCIS) are treated with radiotherapy to reduce their risk of local invasive recurrence after breast-conserving surgery. However, the association of radiotherapy with breast cancer survival in patients with DCIS has not yet been clearly established. Objective: To determine the extent to which radiotherapy is associated with reduced risk of breast cancer mortality in a large cohort of patients treated for DCIS, using a propensity score-based matching approach. Design, Setting, and Participants: This cohort study of women who had first primary DCIS diagnosed between 1998 and 2014 used data from the Surveillance, Epidemiology, and End Results 18 registries database. Information on age and year of diagnosis, ethnicity, income, tumor size, tumor grade, estrogen receptor status, all treatments (surgery and radiation), and outcomes (invasive local recurrence and death from breast cancer) was abstracted for 140 366 women diagnosed with first primary DCIS. Three separate comparisons were performed using 1:1 matching: lumpectomy with radiation vs lumpectomy alone; lumpectomy alone vs mastectomy; and lumpectomy with radiation vs mastectomy. Exposures: Use of radiotherapy and/or extent of surgery. Main Outcomes and Measures: Crude and adjusted 15-year breast cancer-specific mortality. Results: Of the 140 366 patients with DCIS in the cohort (109 712 [78.2%] white; mean [SD] age, 58.8 [12.3] years), 35 070 (25.0%) were treated with lumpectomy alone, 65 301 (46.5%) were treated with lumpectomy and radiotherapy, and 39 995 (28.5%) were treated with mastectomy. The actuarial 15-year breast cancer mortality rate was 2.33% for patients treated with lumpectomy alone, 1.74% for patients treated with lumpectomy and radiation, and 2.26% for patients treated with mastectomy. The adjusted hazard ratios for death were 0.77 (95% CI, 0.67-0.88) for lumpectomy and radiotherapy vs lumpectomy alone (29 465 propensity-matched pairs), 0.91 (95% CI, 0.78-1.05) for mastectomy alone vs lumpectomy alone (20 832 propensity-matched pairs), and 0.75 (95% CI, 0.65-0.87) for lumpectomy and radiotherapy vs mastectomy (29 865 propensity-matched pairs). Conclusions and Relevance: In patients with DCIS, treatment with lumpectomy and radiotherapy was associated with a significant reduction in breast cancer mortality compared with either lumpectomy alone or mastectomy alone. This suggests that the survival benefit of radiation is likely not due to local control, but rather to systemic effects.

Impact of microinvasion on breast cancer mortality in women with ductal carcinoma in situ.

BACKGROUND: Ductal carcinoma in situ (DCIS) is a neoplastic proliferation of epithelial cells which is confined within the basement membrane of the mammary ductal-lobular system. It is of interest to determine to what extent the potential to metastasize increases for DCIS patients when the basement membrane is breached (i.e. microinvasion is present). METHODS: We retrieved the records of 525,395 women who had either first primary DCIS or small (≤ 2.0 cm) node-negative invasive breast cancer in the Surveillance, Epidemiology and End Results (SEER) registries database (1990-2013). For each patient, we extracted information on year of diagnosis, age at diagnosis, tumour size, tumour grade, oestrogen receptor status, use of radiotherapy, type of surgery, cause of death and follow-up time. We classified patients into four groups, according to the size of the invasive component of the primary tumour. We estimated the actuarial rate of breast cancer-specific mortality at ten and 20 years for women in each size category. RESULTS: We identified 161,394 women with pure DCIS, 13,489 women with microinvasive carcinoma (≤ 0.1 cm of invasion), 153,856 women with invasive cancer 0.2-1.0 cm in size and 196,656 women with invasive cancer 1.1-2.0 cm in size. The 20-year actuarial breast cancer-specific mortality rate was 3.8% for women with pure DCIS, was 6.9% for women with microinvasive carcinoma, was 6.8% for women with invasive cancer 0.2-1.0 cm in size and was 12.1% for women with invasive cancer 1.1-2.0 cm in size. The adjusted hazard ratio for death associated with microinvasive carcinoma (vs. pure DCIS) was 2.00 (95% CI 1.76-2.26; p < 0.0001). CONCLUSIONS: In terms of prognosis, microinvasive cancer more closely resembles small invasive cancer 0.2-1.0 cm) than pure DCIS. For invasive cancers under 1.0 cm, size has little impact on mortality.

The prognostic effect of estrogen receptor status differs for younger versus older breast cancer patients.

PURPOSE: To estimate the prognostic impact of estrogen receptor (ER)-status among women with primary invasive breast cancer, according to age at diagnosis. METHODS: We studied 1910 women with primary invasive breast cancer (stages I-III) who were treated at Women's College Hospital between 1987 and 2000. For each patient, we obtained information on age at diagnosis, tumour size, lymph node status, ER-status, treatments received (radiotherapy, chemotherapy and tamoxifen) and dates and causes of death. Patients were followed from the date of diagnosis until the date of death from breast cancer or the date of last follow-up. We used the Kaplan-Meier method to estimate the 15-year actuarial rates of breast cancer-specific survival for women with ER-positive and ER-negative breast cancer, according to age at diagnosis (categories). We used the Cox proportional hazards model to estimate the adjusted hazard ratios for death from breast cancer associated with positive ER-status (compared to negative ER-status), stratified by age at diagnosis. RESULTS: We identified 1347 women with ER-positive breast cancer (70.5%) and 563 women with ER-negative breast cancer (29.5%). Among all 1910 women in the cohort, the actuarial rate of breast cancer-specific survival at 15 years was 77% for those with ER-positive breast cancer compared to 70% for those with ER-negative breast cancer (adjusted HR = 0.69; 95% CI 0.56-0.85; p = 0.0006). The prognostic impact of ER-status differed according to age at diagnosis. Among 213 women diagnosed before age 40, breast cancer-specific survival at 15 years was worse for those with ER-positive breast cancer than for those with ER-negative breast cancer (55 vs. 61%; adjusted HR = 0.90; 95% CI 0.57-1.41; p = 0.64). In contrast, among 1697 women diagnosed between ages 40 and 75, breast cancer-specific survival at 15 years was better for those with ER-positive breast cancer than for those with ER-negative breast cancer (78 vs. 72%; adjusted HR = 0.60; 95% CI 0.47-0.76; p < 0.0001). CONCLUSIONS: Positive ER-status is a favourable prognostic factor among women diagnosed with breast cancer at or above age 40, but not among women diagnosed before age 40.

Which women decide to take tamoxifen?

PURPOSE: To identify factors which predict, among estrogen receptor (ER)-positive breast cancer patients, who chooses to take adjuvant tamoxifen. METHODS: We studied 1347 women with ER-positive breast cancer who were treated at Women's College Hospital between 1987 and 2000. For each patient, we obtained information on age at diagnosis, tumour size, lymph node status, ER status, treatments received and dates of local recurrence and of death. We compared women who did and who did not take tamoxifen for a range of factors. We used the Kaplan-Meier method to estimate 15-year local recurrence-free and breast cancer-specific survival rates for women who did and who did not take tamoxifen. RESULTS: Overall, 50.4% of women who had a mastectomy took tamoxifen and 61.0% of women who had a lumpectomy took tamoxifen (p = 0.002). Tamoxifen use did not correlate with any of the factors that were predictive of a high risk of death from breast cancer, such as young age, large tumour size and positive lymph node status. Young women (<40 years) experienced much higher mortality (41.1%) than older (>60 years) women (14.1%, p < 0.01), but were much less likely to have taken tamoxifen (35.0 vs. 74.6%, p < 0.01). CONCLUSIONS: Approximately one-half of women with ER-positive breast cancer who are candidates for tamoxifen did not take tamoxifen. Women with lumpectomy were more likely to take tamoxifen than women with mastectomy. Paradoxically, women at high risk of death from breast cancer (less than 40 at diagnosis and/or lymph node positive) and who are expected to receive the greatest benefit from tamoxifen in terms of mortality reduction were less likely to take it than were low-risk women (older women, lymph node negative). These findings suggest that women consider the reduction in risk from local recurrence to be more important than the reduction in risk of death from breast cancer when they consider taking tamoxifen.